Crosslinked polymeric network and use thereof

ABSTRACT

A packaging system for the storage of an ophthalmic device includes a sealed container containing one or more unused ophthalmic devices immersed in an aqueous packaging solution comprising one or more crosslinked polymeric networks. The one or more crosslinked polymeric network comprises a reaction product of a first glycosaminoglycan, a second glycosaminoglycan, and a first crosslinking agent, wherein the first glycosaminoglycan is different than the second glycosaminoglycan. The aqueous packaging solution has an osmolality of at least about 180 mOsm/kg, a pH of about 6 to about 9 and is heat sterilized.

PRIORITY CLAIM

The present application is a divisional application of U.S. Ser. No.17/533,454, filed Nov. 23, 2021, now issued as U.S. Pat. No. 11,421,047,which is a divisional application of U.S. Ser. No. 16/739,547, filedJan. 10, 2020, now issued as U.S. Pat. No. 11,732,060, which claimspriority to U.S. Provisional Patent Application Ser. No. 62/798,668,filed Jan. 30, 2019, and entitled “Crosslinked Polymeric Network and UseThereof,” the contents of each being incorporated by reference herein intheir entirety.

BACKGROUND

The present invention generally relates to a crosslinked polymer networkand its use.

It is highly desirable that a contact lens be as comfortable as possiblefor wearers. Manufacturers of contact lenses are continually working toimprove the comfort of the lenses. Nevertheless, many people who wearcontact lenses still experience dryness or eye irritation throughout theday and particularly towards the end of the day. An insufficientlywetted lens at any point in time will cause significant discomfort tothe lens wearer. Although wetting drops can be used as needed toalleviate such discomfort, it would certainly be desirable if suchdiscomfort did not arise in the first place.

Glycosaminoglycans (GAGs) are a group of polysaccharides built ofrepeating disaccharide units. Due to high polarity and water affinity,they can be found in many systems of human bodies. For example, GAGsoccur on the surface of cells and in the extracellular matrix of animalorganisms such as skin, cartilage, and lungs.

GAGs each have a chemical structure including a repeating basaldisaccharide structure consisting of uronic acid and hexosamine andbeing optionally sulfated to various degrees. GAGs are mainlyclassified, depending on the disaccharides constituting them, into threegroups: a first group of compounds composed of chondroitin sulfate ordermatan sulfate, a second group of compounds composed of heparansulfate or heparin, and a third group of hyaluronic acid compounds. Forexample, the compounds composed of chondroitin sulfate or dermatansulfate consist of a disaccharide:uronic acid (glucuronic acid oriduronic acid) (β1→3) N-acetylgalactosamine, the compounds composed ofheparan sulfate or heparin consist of a disaccharide:uronic acid(glucuronic acid or iduronic acid) (β1→4) N-acetylglucosamine, and thehyaluronic acid consists of a disaccharide:glucuronic acid (β1→3)N-acetylglucosamine. In addition, the structure is highly diverse due toa combination with modification by sulfation.

These GAGs are known as important biological materials having bothphysicochemical properties derived from characteristic viscoelasticityand biological properties mediated by interactions with variousfunctional proteins, depending on the molecular size and the sulfationpattern.

It would be desirable to provide improved GAGs that can make abiomedical device such as a contact lens as comfortable as possible forthe wearer and exhibit suitable physical and chemical properties, e.g.,lubriciousness and wettability.

SUMMARY

In accordance with one embodiment of the present invention, acrosslinked polymeric network is provided comprising a reaction productof a first glycosaminoglycan, a second glycosaminoglycan, and one ormore crosslinking agents, wherein the first glycosaminoglycan isdifferent than the second glycosaminoglycan.

In accordance with a second embodiment of the present invention, acrosslinked polymeric network is provided comprising a firstglycosaminoglycan crosslinked with a second glycosaminoglycan, whereinthe first glycosaminoglycan is different than the secondglycosaminoglycan.

In accordance with a third embodiment of the present invention, abiomedical device having a coating on a surface thereof is provided, thecoating comprising one or more crosslinked polymeric networks comprisinga reaction product of a first glycosaminoglycan, a secondglycosaminoglycan, and one or more crosslinking agents, wherein thefirst glycosaminoglycan is different than the second glycosaminoglycan.

In accordance with a fourth embodiment of the present invention, apackaging system for the storage of an ophthalmic device is providedcomprising a sealed container containing one or more unused ophthalmicdevices immersed in an aqueous packaging solution comprising one or morecrosslinked polymeric networks comprising a reaction product of a firstglycosaminoglycan, a second glycosaminoglycan, and one or morecrosslinking agents, wherein the first glycosaminoglycan is differentthan the second glycosaminoglycan, wherein the solution has anosmolality of at least about 200 mOsm/kg, a pH of about 6 to about 9 andis heat sterilized.

In accordance with a fifth embodiment of the present invention, a methodof preparing a package comprising a storable, sterile ophthalmic deviceis provided, the method comprising: (a) immersing an ophthalmic devicein an aqueous packaging solution comprising one or more crosslinkedpolymeric networks comprising a reaction product of a firstglycosaminoglycan, a second glycosaminoglycan, and one or morecrosslinking agents, wherein the first glycosaminoglycan is differentthan the second glycosaminoglycan, wherein the solution has anosmolality of at least about 200 mOsm/kg and a pH in the range of about6 to about 9; (b) packaging the solution and the device in a mannerpreventing contamination of the device by microorganisms; and (c)sterilizing the packaged solution and device.

In accordance with a sixth embodiment of the present invention, anaqueous ophthalmic composition is provided comprising one or morecrosslinked polymeric networks comprising a reaction product of a firstglycosaminoglycan, a second glycosaminoglycan, and one or morecrosslinking agents, wherein the first glycosaminoglycan is differentthan the second glycosaminoglycan, wherein the aqueous ophthalmiccomposition has an osmolality in a range from 200 mOsmol/kg to 400mOsmol/kg.

In accordance with a seventh embodiment of the present invention, a gelcomposition for promoting wound healing is provided wherein the gelcomposition comprises one or more crosslinked polymeric networkscomprising a reaction product of a first glycosaminoglycan, a secondglycosaminoglycan, and one or more crosslinking agents, wherein thefirst glycosaminoglycan is different than the second glycosaminoglycan.

In accordance with an eighth embodiment of the present invention, awound dressing is provided comprising a gel composition comprising oneor more crosslinked polymeric networks comprising a reaction product ofa first glycosaminoglycan, a second glycosaminoglycan, and one or morecrosslinking agents, wherein the first glycosaminoglycan is differentthan the second glycosaminoglycan.

The crosslinked polymeric networks of the present inventionadvantageously exhibit suitable physical and chemical properties, e.g.,oxygen permeability, lubriciousness mucoadhesivity and wettability, forprolonged contact with the body by crosslinking a firstglycosaminoglycan with a second glycosaminoglycan, wherein the firstglycosaminoglycan is different than the second glycosaminoglycan. Thecrosslinked polymeric networks of the present invention advantageouslyprovide improved lubricity to the surface of a biomedical device such asa contact lens. For example, the benefits of improved lubricity usingthe crosslinked polymeric networks of the present invention include, forexample, minimizing interactions between a contact lens and itsrespective packaging blister, a lens surface that is more robust towardprocessing and handling conditions, and improved comfort upon insertioninto a subject's eye, as well as reduced deposition (e.g., protein,lipid) and thus potentially reducing biofilm formation by the contactlens wearer onto the lens surface.

In addition, the crosslinked polymeric networks of the present inventionadvantageously provide improved wettability to the surface of abiomedical device such as a contact lens. It is believed that thebenefits of having improved wettability using the crosslinked polymericnetworks of the present invention include, for example, delayingevaporation of the aqueous layer of the device due to its effectlike-coating on the ocular surface and moisturizing properties and thuspotentially relieving dry eye symptoms.

DETAILED DESCRIPTION

The illustrative embodiments described herein are directed to acrosslinked polymeric network useful in treating the surface of abiomedical device intended for direct contact with body tissue or fluid.In general, the crosslinked polymeric network comprises a reactionproduct of a first glycosaminoglycan (GAG), a second glycosaminoglycan,and one or more crosslinking agents, wherein the first glycosaminoglycanis different than the second glycosaminoglycan. A GAG is one moleculewith many alternating subunits. In general, GAGs are represented by theformula A-B-A-B-A-B, where A is an uronic acid and B is an amino sugarthat is either O- or N-sulfated, where the A and B units can beheterogeneous with respect to epimeric content or sulfation. Any naturalor synthetic polymer containing uronic acid can be used. Other GAGs aresulfated at different sugars. There are many different types of GAGshaving commonly understood structures such as, for example, chondroitinsulfate, dermatan, heparan, heparin, dermatan sulfate, hyaluronic acidor a salt thereof, e.g., sodium hyaluronate or potassium hyaluronate,heparan sulfate, and other disaccharides such as sucrose, lactulose,lactose, maltose, trehalose, cellobiose, mannobiose and chitobiose.Glycosaminoglycans can be purchased from Sigma, and many otherbiochemical suppliers.

In one embodiment, the first GAG is hyaluronic acid or a salt thereofand the second GAG is chondroitin sulfate. Hyaluronic acid is awell-known, naturally occurring, water soluble biodegradable polymercomposed of two alternatively linked sugars, D-glucuronic acid andN-acetylglucosamine, linked via alternating β-(1,4) and β-(1,3)glycosidic bonds. Hyaluronic acid is a non-sulfated GAG. Hyaluronan. Thepolymer is hydrophilic and highly viscous in aqueous solution atrelatively low solute concentrations. It often occurs naturally as thesodium salt, sodium hyaluronate. Methods of preparing commerciallyavailable hyaluronan and salts thereof are well known. Hyaluronan can bepurchased from Seikagaku Company, Clear Solutions Biotech, Inc.,Pharmacia Inc., Sigma Inc., and many other suppliers. Hyaluronic acidhas one or more repeating units of the structure represented by thefollowing formula:

Accordingly, the repeating units in hyaluronic acid can be as follows:

In general, hyaluronic acid or a salt thereof can have from about 2 toabout 1,500,000 disaccharide units. In one embodiment, hyaluronic acidor a salt thereof can have a weight average molecular weight rangingfrom about 10,000 to about 3,000,000 Daltons (Da) in which the lowerlimit is from about 10,000, about 20,000, about 30,000, about 40,000,about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, orabout 100,000, and the upper limit is about 200,000, about 300,000,about 400,000, about 500,000, about 600,000, about 700,000, about800,000, about 900,000, about 1,000,000, or about up to 2,800,000, whereany of the lower limits can be combined with any of the upper limits.

Chondroitin sulfate is a linear sulfated polysaccharide composed ofrepeating β-D-glucuronic acid (GlcA) and N-acetyl-β-D-galactosamine(GalNAc) units arranged in the sequence by GlcA-β(1,3)-GalNAc-β(1,4)glycosidic bonds. In one embodiment, chondroitin sulfate has one or morerepeating units of the structure represented by the following formula:

In one embodiment, chondroitin sulfate has one or more repeating unitsof the structure represented by the following formula:

In general, chondroitin sulfate can have from about 2 to about 1,500,000repeating units. In one embodiment, chondroitin sulfate can have aweight average molecular weight ranging from about 10,000 to about3,000,000 Da in which the lower limit is from about 5,000, 10,000, about20,000, about 30,000, about 40,000, about 50,000, about 60,000, about70,000, about 80,000, about 90,000, or about 100,000, and the upperlimit is about 200,000, about 300,000, about 400,000, about 500,000,about 600,000, about 700,000, about 800,000, about 900,000, about1,000,000, or about 3,000,000 where any of the lower limits can becombined with any of the upper limits or any of the upper limits can becombined with any of the upper limits.

As discussed hereinabove, the reaction product includes one or morecrosslinking agents, e.g., to crosslink the first glycosaminoglycan withthe second glycosaminoglycan. The crosslinking agents for use herein canbe any suitable crosslinking agent known in the art. In general, asuitable crosslinking agent is, for example, a crosslinking agent havingcomplimentary functional groups to the first glycosaminoglycan such ashyaluronic acid and to the second glycosaminoglycan such as chondroitinsulfate. In one embodiment, a suitable crosslinking agent includes, forexample, a bi- or polyfunctional crosslinking agent. The bi- orpolyfunctional crosslinking agent connects the first glycosaminoglycanwith the second glycosaminoglycan. In addition, the bi- orpolyfunctional crosslinking agent further acts as a spacer between thefirst glycosaminoglycan and the second glycosaminoglycan. In general,the bi- or polyfunctional crosslinking agent comprises two or morefunctional groups capable of reacting with functional groups of thefirst glycosaminoglycan such as hyaluronic acid and the secondglycosaminoglycan such as chondroitin sulfate, resulting in theformation of covalent bonds.

Suitable bi- or polyfunctional crosslinking agents include, for example,divinyl sulfone, diepoxides, multiepoxides, dihydrazides, dihydricalcohols, polyhydric alcohols, polyhydric thiols, anhydrides,carbodiimides, polycarboxylic acids, carboxymethyl thiols, cysteine, andcysteine-like amino acids and the like. In one embodiment, a bi- orpolyfunctional crosslinking agent is a bis- or polyepoxide, such asdiglycidyl ether derivatives. According to an embodiment, the bi- orpolyfunctional epoxide crosslinking agent comprises two or more glycidylether functional groups. The glycidyl ether functional groups react withprimary hydroxyl groups of the hyaluronic acid and the chondroitinsulfate, resulting in the formation of ether bonds. In one embodiment,suitable bis- or polyfunctional crosslinking agents include, forexample, 1,4-butanediol diglycidyl ether (BDDE),1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE), ethylene glycol diglycidylether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE), diepoxyoctane,1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether,polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidylether, polyglycerol polyglycidyl ester, diglycerol polyglycidyl ether,glycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether,pentaerythritol polyglyglycidyl ether, sorbitol polyglycidyl ether,1,2,7,8-diepoxyoctane, 1,3-butadiene diepoxide, pentaerythritoltetraglycidyl ether, polyepoxides and the like.

Suitable dihydrazide crosslinking agents include, for example, succinicacid dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide,pimelic acid dihydrazide, suberic acid dihydrazide, azalaic aciddihydrazide, sebacic acid dihydrazide, undecanedioic acid dihydrazide,dodecanedioic acid dihydrazide, brassylic acid dihydrazide,tetradecanedioic acid dihydrazide, pentadecanedioic acid dihydrazide,thapsic acid dihydrazide, octadecanedioic acid dihydrazide and the like.

Suitable dihydric alcohol crosslinking agents include, for example,ethylene glycol, propylene glycol, butylene glycol diethylene glycol,dipropylene glycol, neopentyl glycol, 1,3-propanediol, hexylene glycol,pentylene glycol, heptylene glycol, octylene glycol and the like.Suitable polyhydric alcohol crosslinking agents include, for exampleglycerin, pentaerythrite, xylitol, galactitol and the like. Suitablecarbodiimide crosslinking agents include, for example, a compound offormula X—N═C═N—X, wherein each X independently is a C₁ to C₆ alkyloptionally substituted with 1-2 dialkylamino groups, or is a C₅ to C₆cycloalkyl group, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride, and cyclohexyl carbodiimide. Suitable anhydridecrosslinking agents include, for example, methacrylic anhydride, octeylsuccinic anhydride and the like. In one embodiment, a suitablecrosslinking agent is an aldehyde crosslinking agent such as, forexample, formaldehyde, gluteraldehyde, gluraraldehyde and the like. Inone embodiment, a suitable crosslinking agent includes, for example, anacid chloride, n-hydroxysuccinimide, polyethylene glycol diacrylates,polyethylene glycol diamines, ureas, diisocyanates and the like.

The crosslinked polymeric network of the present invention can beobtained by forming a solution of the first glycosaminoglycan and secondglycosaminoglycan, and adding the foregoing one or more crosslinkingagents. The solution is stirred for a suitable time sufficient tocrosslink at least the first glycosaminoglycan with the secondglycosaminoglycan. In one embodiment, crosslinking between theglycosaminoglycans can take place between 1° C. and about 99° C. over atime period of about 2 hours to about 24 hours.

The solution can contain a suitable solvent such as, for example, water,crown-ethers, dimethyl sulphoxide (DMSO), dimethyl formamide (DMF) andother aprotic solvents. In general, the amount of the firstglycosaminoglycan can range from about 0.010 to about 50 wt. %, based onthe total weight of the solution. In one embodiment, the amount of thefirst glycosaminoglycan can range from about 0.1 to about 5 wt. %, basedon the total weight of the solution. In one embodiment, the amount ofthe second glycosaminoglycan can range from about 0.01 to about 50 wt.%, based on the total weight of the solution. In one embodiment, theamount of the second glycosaminoglycan can range from about 0.1 to about5 wt. %, based on the total weight of the solution. The crosslinkingagent can be added to the solution in an amount ranging from about 0.05to about 10 wt. %, based on the total weight of the solution.

It will be readily understood and appreciated by those skilled in theart that the reaction product constitutes a complex mixture of compoundsincluding, for example, the first glycosaminoglycan crosslinked with thesecond glycosaminoglycan, the first glycosaminoglycan crosslinked withthe first glycosaminoglycan, the second glycosaminoglycan crosslinkedwith the second glycosaminoglycan, unreacted first glycosaminoglycan andunreacted second glycosaminoglycan. For example, in one illustrativeembodiment, a first glycosaminoglycan crosslinked with a secondglycosaminoglycan can have a weight average molecular weight rangingfrom about 20,000 to about 6,000,000 Da in which the lower limit is fromabout 20,000, about 30,000, about 40,000, about 50,000, about 60,000,about 70,000, about 80,000, about 90,000, or about 100,000 Da, and theupper limit is about 200,000, about 300,000, about 400,000, about500,000, about 600,000, about 700,000, about 800,000, about 900,000,about 1,000,000, about 2,000,000, about 3,000,000, about 4,000,000,about 5,000,000 or up to about 6,000,000 Da where any of the lowerlimits can be combined with any of the upper limits. It is not necessaryto isolate one or more specific components of the reaction productmixture. Indeed, the reaction product mixture can be employed as is.

In one embodiment, the crosslinked polymeric network of the presentinvention can be further crosslinked with one or more of the same ordifferent third glycosaminoglycans. In general, the one or more thirdglycosaminoglycans can be any of the glycosaminoglycans discussedhereinabove. In one embodiment, the one or more third glycosaminoglycansare hyaluronic acid. In one embodiment, the one or more thirdglycosaminoglycans are chondroitin sulfate. In one embodiment, the oneor more third glycosaminoglycans include hyaluronic acid and chondroitinsulfate.

The crosslinking agent for crosslinking the one or more of the same ordifferent third glycosaminoglycans with the foregoing the crosslinkedpolymeric network can be any of the crosslinking agents discussed above.As one skilled in the art will understand, the crosslinking agent canthe same crosslinking agent or a different crosslinking agent as thecrosslinking agent used in the foregoing reaction product.

In general, the crosslinked polymeric network of the present inventioncan be further crosslinked with one or more of the same or differentthird glycosaminoglycans in substantially the same manner as discussedabove.

In one embodiment, the crosslinked polymeric network of the presentinvention can be further mixed with one or more of the same or differentthird glycosaminoglycans. In general, the one or more thirdglycosaminoglycans can be any of the glycosaminoglycans discussedhereinabove. In one embodiment, the one or more third glycosaminoglycansare linear glycosaminoglycans. In one embodiment, the linearglycosaminoglycan is linear hyaluronic acid. In one embodiment, thelinear glycosaminoglycan is linear chondroitin sulfate. In general, theone or more third glycosaminoglycans can be mixed with the crosslinkedpolymeric network of the present invention in an amount ranging fromabout 1 wt. % to about 20 wt. %, based on the total weight of themixture. In one embodiment, the one or more third glycosaminoglycans canbe mixed with the crosslinked polymeric network of the present inventionin an amount ranging from about 1 wt. % to about 10 wt. %, based on thetotal weight of the mixture. In one embodiment, the one or more thirdglycosaminoglycans can be mixed with the crosslinked polymeric networkof the present invention in an amount ranging from about 1 wt. % toabout 5 wt. %, based on the total weight of the mixture.

In another embodiment of the present invention, a biomedical device isprovided which comprise the crosslinked polymeric networks of thepresent invention at their surfaces. The crosslinked polymeric networkmay be provided over the entire surface of the biomedical device or overonly a portion of the biomedical device surface. The crosslinkedpolymeric network may also be provided within the construct of thebiomedical device. As used herein, the term “biomedical device” shall beunderstood to mean any article that is designed to be used while eitherin or on mammalian tissues or fluid, and preferably in or on humantissue or fluids. Representative examples of biomedical devices include,but are not limited to, artificial ureters, diaphragms, intrauterinedevices, heart valves, catheters, denture liners, prosthetic devices,ophthalmic lens applications, where the lens is intended for directplacement in or on the eye, such as, for example, intraocular devicesand contact lenses. The preferred biomedical devices are ophthalmicdevices, particularly contact lenses, and most particularly contactlenses made from silicone hydrogels.

As used herein, the term “ophthalmic device” refers to devices thatreside in or on the eye. These devices can provide optical correction,wound care, tissue repair, drug delivery, diagnostic functionality orcosmetic enhancement or effect or a combination of these properties.Useful ophthalmic devices include, but are not limited to, ophthalmiclenses such as soft contact lenses, e.g., a soft, hydrogel lens; soft,non-hydrogel lens and the like, hard contact lenses, e.g., a hard, gaspermeable lens material and the like, intraocular lenses, overlaylenses, ocular inserts, optical inserts, viscoelastics and the like. Asis understood by one skilled in the art, a lens is considered to be“soft” if it can be folded back upon itself without breaking.

The biomedical devices to be surface modified according to the presentinvention can be any material known in the art capable of forming abiomedical device as described above. In one embodiment, a biomedicaldevice includes devices formed from material not hydrophilic per se.Such devices are formed from materials known in the art and include, byway of example, polysiloxanes, perfluoropolyethers, fluorinatedpoly(meth)acrylates or equivalent fluorinated polymers derived, e.g.,from other polymerizable carboxylic acids, polyalkyl (meth)acrylates orequivalent alkylester polymers derived from other polymerizablecarboxylic acids, or fluorinated polyolefins, such as fluorinatedethylene propylene polymers, or tetrafluoroethylene, preferably incombination with a dioxol, e.g., perfluoro-2,2-dimethyl-1,3-dioxol.Representative examples of suitable bulk materials include, but are notlimited to, Lotrafilcon A, Neofocon, Pasifocon, Telefocon, Silafocon,Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon, Fluorofocon orTeflon AF materials, such as Teflon AF 1600 or Teflon AF 2400 which arecopolymers of about 63 to about 73 mol % ofperfluoro-2,2-dimethyl-1,3-dioxol and about 37 to about 27 mol % oftetrafluoroethylene, or of about 80 to about 90 mol % ofperfluoro-2,2-dimethyl-1,3-dioxol and about 20 to about 10 mol % oftetrafluoroethylene.

In another embodiment, a biomedical device includes a device formed frommaterial hydrophilic per se, since reactive groups, e.g., carboxy,carbamoyl, sulfate, sulfonate, phosphate, amine, ammonium or hydroxygroups, are inherently present in the material and therefore also at thesurface of a biomedical device manufactured therefrom. Such devices areformed from materials known in the art and include, by way of example,polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyvinylpyrrolidone (PVP), polyacrylic acid, polymethacrylic acid,polyacrylamide, polydimethylacrylamide (DMA), polyvinyl alcohol and thelike and copolymers thereof, e.g., from two or more monomers selectedfrom hydroxyethyl acrylate, hydroxyethyl methacrylate, N-vinylpyrrolidone, acrylic acid, methacrylic acid, acrylamide, dimethylacrylamide, vinyl alcohol and the like. Representative examples ofsuitable bulk materials include, but are not limited to, Polymacon,Tefilcon, Methafilcon, Deltafilcon, Bufilcon, Phemfilcon, Ocufilcon,Focofilcon, Etafilcon, Hefilcon, Vifilcon, Tetrafilcon, Perfilcon,Droxifilcon, Dimefilcon, Isofilcon, Mafilcon, Nelfilcon, Atlafilcon andthe like. Examples of other suitable bulk materials include BalafilconA, Hilafilcon A, Alphafilcon A, Bilafilcon B and the like.

In another embodiment, a biomedical device to be surface modifiedaccording to the present invention include a device which is formed frommaterial which are amphiphilic segmented copolymers containing at leastone hydrophobic segment and at least one hydrophilic segment which arelinked through a bond or a bridge member.

It is particularly useful to employ biocompatible materials hereinincluding both soft and rigid materials commonly used for ophthalmiclenses, including contact lenses. In general, non-hydrogel materials arehydrophobic polymeric materials that do not contain water in theirequilibrium state. Typical non-hydrogel materials comprise siliconeacrylics, such as those formed bulky silicone monomer (e.g.,tris(trimethylsiloxy)silylpropyl methacrylate, commonly known as “TRIS”monomer), methacrylate end-capped poly(dimethylsiloxane) prepolymer, orsilicones having fluoroalkyl side groups (polysiloxanes are alsocommonly known as silicone polymers).

On the other hand, hydrogel materials comprise hydrated, crosslinkedpolymeric systems containing water in an equilibrium state. Hydrogelmaterials contain about 5 wt. % water or more (up to, for example, about80 wt. %). The preferred hydrogel materials, include silicone hydrogelmaterials. In one preferred embodiment, materials include vinylfunctionalized polydimethylsiloxanes copolymerized with hydrophilicmonomers as well as fluorinated methacrylates and methacrylatefunctionalized fluorinated polyethylene oxides copolymerized withhydrophilic monomers. Representative examples of suitable materials foruse herein include those disclosed in U.S. Pat. Nos. 5,310,779;5,387,662; 5,449,729; 5,512,205; 5,610,252; 5,616,757; 5,708,094;5,710,302; 5,714,557 and 5,908,906, the contents of which areincorporated by reference herein.

In one embodiment, hydrogel materials for biomedical devices, such ascontact lenses, can contain a hydrophilic monomer such as one or moreunsaturated carboxylic acids, vinyl lactams, amides, polymerizableamines, vinyl carbonates, vinyl carbamates, oxazolone monomers,copolymers thereof and the like and mixtures thereof. Useful amidesinclude acrylamides such as N,N-dimethylacrylamide andN,N-dimethylmethacrylamide. Useful vinyl lactams include cyclic lactamssuch as N-vinyl-2-pyrrolidone. Examples of other hydrophilic monomersinclude hydrophilic prepolymers such as poly(alkene glycols)functionalized with polymerizable groups. Examples of usefulfunctionalized poly(alkene glycols) include poly(diethylene glycols) ofvarying chain length containing monomethacrylate or dimethacrylate endcaps. In a preferred embodiment, the poly(alkene glycol) polymercontains at least two alkene glycol monomeric units. Still furtherexamples are the hydrophilic vinyl carbonate or vinyl carbamate monomersdisclosed in U.S. Pat. No. 5,070,215, and the hydrophilic oxazolonemonomers disclosed in U.S. Pat. No. 4,910,277. Other suitablehydrophilic monomers will be apparent to one skilled in the art. Inanother embodiment, a hydrogel material can contain asiloxane-containing monomer and at least one of the aforementionedhydrophilic monomers and/or prepolymers.

Non-limited examples of hydrophobic monomers are C₁-C₂₀ alkyl and C₃-C₂₀cycloalkyl (meth)acrylates, substituted and unsubstituted aryl(meth)acrylates (wherein the aryl group comprises 6 to 36 carbon atoms),(meth) acrylonitrile, styrene, lower alkyl styrene, lower alkyl vinylethers, and C₂-C₁₀ perfluoroalkyl (meth)acrylates and correspondinglypartially fluorinate (meth)acrylates.

A wide variety of materials can be used herein, and silicone hydrogelcontact lens materials are particularly preferred. Silicone hydrogelsgenerally have a water content greater than about 5 wt. % and morecommonly between about 10 to about 80 wt. %. Such materials are usuallyprepared by polymerizing a mixture containing at least onesilicone-containing monomer and at least one hydrophilic monomer.Typically, either the silicone-containing monomer or the hydrophilicmonomer functions as a crosslinking agent (a crosslinker being definedas a monomer having multiple polymerizable functionalities) or aseparate crosslinker may be employed. Applicable silicone-containingmonomers for use in the formation of silicone hydrogels are well knownin the art and numerous examples are provided in U.S. Pat. Nos.4,136,250; 4,153,641; 4,740,533; 5,034,461; 5,070,215; 5,260,000;5,310,779; and 5,358,995.

Representative examples of applicable silicone-containing monomersinclude bulky polysiloxanylalkyl(meth)acrylic monomers. An example of abulky polysiloxanylalkyl(meth)acrylic monomer is represented by thestructure of Formula I:

wherein X denotes —O— or —NR— wherein R denotes hydrogen or a C₁-C₄alkyl; each R¹ independently denotes hydrogen or methyl; each R²independently denotes a lower alkyl radical, phenyl radical or a grouprepresented by

wherein each R^(2′) independently denotes a lower alkyl or phenylradical; and h is 1 to 10.

Representative examples of other applicable silicone-containing monomersinclude, but are not limited to, bulky polysiloxanylalkyl carbamatemonomers as generally depicted in Formula Ia:

wherein X denotes —NR—; wherein R denotes hydrogen or a C₁-C₄ alkyl; R¹denotes hydrogen or methyl; each R² independently denotes a lower alkylradical, phenyl radical or a group represented by

wherein each R^(2′) independently denotes a lower alkyl or phenylradical; and h is 1 to 10, and the like.

Examples of bulky monomers are3-methacryloyloxypropyltris(trimethylsiloxy)silane ortris(trimethylsiloxy)silylpropyl methacrylate, sometimes referred to asTRIS and tris(trimethylsiloxy)silylpropyl vinyl carbamate, sometimesreferred to as TRIS-VC and the like and mixtures thereof.

Such bulky monomers may be copolymerized with a silicone macromonomer,which is a poly(organosiloxane) capped with an unsaturated group at twoor more ends of the molecule. U.S. Pat. No. 4,153,641 discloses, forexample, various unsaturated groups such as acryloxy or methacryloxygroups.

Another class of representative silicone-containing monomers includes,but is not limited to, silicone-containing vinyl carbonate or vinylcarbamate monomers such as, for example,1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]tetramethyl-disiloxane;3-(trimethylsilyl)propyl vinyl carbonate;3-(vinyloxycarbonylthio)propyl-[tris(trimethylsiloxy)silane];3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate;3-[tris(trimethylsiloxy)silyl]propyl allyl carbamate;3-[tris(trimethylsiloxy)silyl]propyl vinyl carbonate;t-butyldimethylsiloxyethyl vinyl carbonate; trimethylsilylethyl vinylcarbonate; trimethylsilylmethyl vinyl carbonate and the like andmixtures thereof.

Another class of silicone-containing monomers includespolyurethane-polysiloxane macromonomers (also sometimes referred to asprepolymers), which may have hard-soft-hard blocks like traditionalurethane elastomers. They may be end-capped with a hydrophilic monomersuch as HEMA. Examples of such silicone urethanes are disclosed in avariety or publications, including Lai, Yu-Chin, “The Role of BulkyPolysiloxanylalkyl Methacrylates in Polyurethane-PolysiloxaneHydrogels,” Journal of Applied Polymer Science, Vol. 60, 1193-1199(1996). PCT Published Application No. WO 96/31792 discloses examples ofsuch monomers, which disclosure is hereby incorporated by reference inits entirety. Further examples of silicone urethane monomers arerepresented by Formulae II and III:E(*D*A*D*G)_(a)*D*A*D*E′; or  (II)E(*D*G*D*A)_(a)*D*A*D*E′; or  (III)wherein:

-   -   D independently denotes an alkyl diradical, an alkyl cycloalkyl        diradical, a cycloalkyl diradical, an aryl diradical or an        alkylaryl diradical having 6 to about 30 carbon atoms;    -   G independently denotes an alkyl diradical, a cycloalkyl        diradical, an alkyl cycloalkyl diradical, an aryl diradical or        an alkylaryl diradical having 1 to about 40 carbon atoms and        which may contain ether, thio or amine linkages in the main        chain;    -   * denotes a urethane or ureido linkage;    -   a is at least 1;    -   A independently denotes a divalent polymeric radical of Formula        IV:

wherein each R^(s) independently denotes an alkyl or fluoro-substitutedalkyl group having 1 to about 10 carbon atoms which may contain etherlinkages between the carbon atoms; m′ is at least 1; and p is a numberthat provides a moiety weight of about 400 to about 10,000;

each of E and E′ independently denotes a polymerizable unsaturatedorganic radical represented by Formula V:

wherein:

-   -   R³ is hydrogen or methyl;    -   R⁴ is hydrogen, an alkyl radical having 1 to 6 carbon atoms, or        a —CO—Y—R⁶ radical wherein Y is —O—, —S— or —NH—;    -   R⁵ is a divalent alkylene radical having 1 to about 10 carbon        atoms;    -   R⁶ is a alkyl radical having 1 to about 12 carbon atoms;    -   X denotes —CO— or —OCO—;    -   Z denotes —O— or —NH—;    -   Ar denotes an aromatic radical having about 6 to about 30 carbon        atoms;    -   w is 0 to 6; x is 0 or 1; y is 0 or 1; and z is 0 or 1.

A preferred silicone-containing urethane monomer is represented byFormula VI:

wherein m is at least 1 and is preferably 3 or 4, a is at least 1 andpreferably is 1, p is a number which provides a moiety weight of about400 to about 10,000 and is preferably at least about 30, R⁷ is adiradical of a diisocyanate after removal of the isocyanate group, suchas the diradical of isophorone diisocyanate, and each E″ is a grouprepresented by:

In another embodiment of the present invention, a silicone hydrogelmaterial comprises (in bulk, that is, in the monomer mixture that iscopolymerized) about 5 to about 50 percent, and preferably about 10 toabout 25, by weight of one or more silicone macromonomers, about 5 toabout 75 percent, and preferably about 30 to about 60 percent, by weightof one or more polysiloxanylalkyl (meth)acrylic monomers, and about 10to about 50 percent, and preferably about 20 to about 40 percent, byweight of a hydrophilic monomer. In general, the silicone macromonomeris a poly(organosiloxane) capped with an unsaturated group at two ormore ends of the molecule. In addition to the end groups in the abovestructural formulas, U.S. Pat. No. 4,153,641 discloses additionalunsaturated groups, including acryloxy or methacryloxy.Fumarate-containing materials such as those disclosed in U.S. Pat. Nos.5,310,779; 5,449,729 and 5,512,205 are also useful substrates inaccordance with the invention. The silane macromonomer may be asilicone-containing vinyl carbonate or vinyl carbamate or apolyurethane-polysiloxane having one or more hard-soft-hard blocks andend-capped with a hydrophilic monomer.

Another class of representative silicone-containing monomers includesfluorinated monomers. Such monomers have been used in the formation offluorosilicone hydrogels to reduce the accumulation of deposits oncontact lenses made therefrom, as disclosed in, for example, U.S. Pat.Nos. 4,954,587; 5,010,141; 5,079,319 and 7,994,356. Also, the use ofsilicone-containing monomers having certain fluorinated side groups,i.e., —(CF₂)—H, have been found to improve compatibility between thehydrophilic and silicone-containing monomeric units. See, e.g., U.S.Pat. Nos. 5,321,108 and 5,387,662.

The above silicone materials are merely exemplary, and other materialsfor use as substrates and have been disclosed in various publicationsand are being continuously developed for use in contact lenses and othermedical devices can also be used. For example, a biomedical device canbe formed from at least a cationic monomer such as cationicsilicone-containing monomer or cationic fluorinated silicone-containingmonomers.

Contact lenses for application of the present invention can bemanufactured employing various conventional techniques, to yield ashaped article having the desired posterior and anterior lens surfaces.Spincasting methods are disclosed in U.S. Pat. Nos. 3,408,429 and3,660,545; and static casting methods are disclosed in U.S. Pat. Nos.4,113,224, 4,197,266 and 5,271,876. Curing of the monomeric mixture maybe followed by a machining operation in order to provide a contact lenshaving a desired final configuration. As an example, U.S. Pat. No.4,555,732 discloses a process in which an excess of a monomeric mixtureis cured by spincasting in a mold to form a shaped article having ananterior lens surface and a relatively large thickness. The posteriorsurface of the cured spincast article is subsequently lathe cut toprovide a contact lens having the desired thickness and posterior lenssurface. Further machining operations may follow the lathe cutting ofthe lens surface, for example, edge-finishing operations.

Typically, an organic diluent is included in the initial monomericmixture in order to minimize phase separation of polymerized productsproduced by polymerization of the monomeric mixture and to lower theglass transition temperature of the reacting polymeric mixture, whichallows for a more efficient curing process and ultimately results in amore uniformly polymerized product. Sufficient uniformity of the initialmonomeric mixture and the polymerized product is of particularimportance for silicone hydrogels, primarily due to the inclusion ofsilicone-containing monomers which may tend to separate from thehydrophilic comonomer.

Suitable organic diluents include, for example, monohydric alcohols suchas C₆-C₁₀ straight-chained aliphatic monohydric alcohols, e.g.,n-hexanol and n-nonanol; diols such as ethylene glycol; polyols such asglycerin; ethers such as diethylene glycol monoethyl ether; ketones suchas methyl ethyl ketone; esters such as methyl enanthate; andhydrocarbons such as toluene. Preferably, the organic diluent issufficiently volatile to facilitate its removal from a cured article byevaporation at or near ambient pressure.

Generally, the diluent may be included at about 5 to about 60 percent byweight of the monomeric mixture, with about 10 to about 50 percent byweight being especially preferred. If necessary, the cured lens may besubjected to solvent removal, which can be accomplished by evaporationat or near ambient pressure or under vacuum. An elevated temperature canbe employed to shorten the time necessary to evaporate the diluent.

Following removal of the organic diluent, the lens can then be subjectedto mold release and optional machining operations. The machining stepincludes, for example, buffing or polishing a lens edge and/or surface.Generally, such machining processes may be performed before or after thearticle is released from a mold part. As an example, the lens may be dryreleased from the mold by employing vacuum tweezers to lift the lensfrom the mold.

As one skilled in the art will readily appreciate, biomedical devicesurface functional groups of the biomedical device according to thepresent invention may be inherently present at the surface of thedevice. However, if the biomedical device contains too few or nofunctional groups, the surface of the device can be modified by knowntechniques, for example, plasma chemical methods (see, for example, WO94/06485), or conventional functionalization with groups such as —OH, or—CO₂H. Suitable biomedical device surface functional groups of thebiomedical device include a wide variety of groups well known to theskilled artisan. Representative examples of such functional groupsinclude, but are not limited to, hydroxy groups, cis 1,2-diols, cis1,3-diols, α hydroxy acid groups (e.g., sialic acid, salicylic acid),carboxylic acids, di-carboxylic acids, catechols, silanols, silicatesand the like.

In one embodiment, the foregoing biomedical devices are subjected to anoxidative surface treatment such as corona discharge or plasma oxidationfollowed by treatment with the crosslinked polymeric network of thepresent invention. For example, a biomedical device such as a siliconehydrogel formulation containing hydrophilic polymers, such aspoly(N,N-dimethylacrylamide) or poly(N-vinylpyrrolidinone), is subjectedto an oxidative surface treatment to form at least silicates on thesurface of the lens and then the lens is treated with an aqueoussolution containing the crosslinked polymeric network of the presentinvention to render a lubricious, stable, highly wettable crosslinkedpolymeric network based surface coating. The complexation treatment isadvantageously performed under autoclave conditions (sterilizationconditions).

The standard process such as a plasma process (also referred to as“electrical glow discharge processes”) provides a thin, durable surfaceupon the biomedical device prior to binding the crosslinked polymericnetwork to at least a portion of the surface thereof. Examples of suchplasma processes are provided in U.S. Pat. Nos. 4,143,949; 4,312,575;and 5,464,667.

Although plasma processes are generally well known in the art, a briefoverview is provided below. Plasma surface treatments involve passing anelectrical discharge through a gas at low pressure. The electricaldischarge may be at radio frequency (typically 13.56 MHz), althoughmicrowave and other frequencies can be used. Electrical dischargesproduce ultraviolet (UV) radiation, in addition to being absorbed byatoms and molecules in their gas state, resulting in energetic electronsand ions, atoms (ground and excited states), molecules, and radicals.Thus, a plasma is a complex mixture of atoms and molecules in bothground and excited states, which reach a steady state after thedischarge is begun. The circulating electrical field causes theseexcited atoms and molecules to collide with one another as well as thewalls of the chamber and the surface of the material being treated.

The deposition of a coating from a plasma onto the surface of a materialhas been shown to be possible from high-energy plasmas without theassistance of sputtering (sputter-assisted deposition). Monomers can bedeposited from the gas phase and polymerized in a low-pressureatmosphere (about 0.005 to about 5 torr, and preferably about 0.001 toabout 1 torr) onto a substrate utilizing continuous or pulsed plasmas,suitably as high as about 1000 watts. A modulated plasma, for example,may be applied about 100 milliseconds on then off. In addition, liquidnitrogen cooling has been utilized to condense vapors out of the gasphase onto a substrate and subsequently use the plasma to chemicallyreact these materials with the substrate. However, plasmas do notrequire the use of external cooling or heating to cause the deposition.Low or high wattage (e.g., about 5 to about 1000, and preferably about20 to about 500 watts) plasmas can coat even the most chemical-resistantsubstrates, including silicones.

After initiation by a low energy discharge, collisions between energeticfree electrons present in the plasma cause the formation of ions,excited molecules, and free-radicals. Such species, once formed, canreact with themselves in the gas phase as well as with furtherground-state molecules. The plasma treatment may be understood as anenergy dependent process involving energetic gas molecules. For chemicalreactions to take place at the surface of the lens, one needs therequired species (element or molecule) in terms of charge state andparticle energy. Radio frequency plasmas generally produce adistribution of energetic species. Typically, the “particle energy”refers to the average of the so-called Boltzman-style distribution ofenergy for the energetic species. In a low-density plasma, the electronenergy distribution can be related by the ratio of the electric fieldstrength sustaining the plasma to the discharge pressure (E/p). Theplasma power density P is a function of the wattage, pressure, flowrates of gases, etc., as will be appreciated by the skilled artisan.Background information on plasma technology, hereby incorporated byreference, includes the following: A. T. Bell, Proc. Intl. Conf. Phenom.Ioniz. Gases, “Chemical Reaction in Nonequilibrium Plasmas”, 19-33(1977); J. M. Tibbitt, R. Jensen, A. T. Bell, M. Shen, Macromolecules,“A Model for the Kinetics of Plasma Polymerization”, 3, 648-653 (1977);J. M. Tibbitt, M. Shen, A. T. Bell, J. Macromol. Sci.-Chem., “StructuralCharacterization of Plasma-Polymerized Hydrocarbons”, A10, 1623-1648(1976); C. P. Ho, H. Yasuda, J. Biomed, Mater. Res., “Ultrathin coatingof plasma polymer of methane applied on the surface of silicone contactlenses”, 22, 919-937 (1988); H. Kobayashi, A. T. Bell, M. Shen,Macromolecules, “Plasma Polymerization of Saturated and UnsaturatedHydrocarbons”, 3, 277-283 (1974); R. Y. Chen, U.S. Pat. No. 4,143,949,Mar. 13, 1979, “Process for Putting a Hydrophilic Coating on aHydrophobic Contact lens”; and H. Yasuda, H. C. Marsh, M. O. Bumgarner,N. Morosoff, J. of Appl. Poly. Sci., “Polymerization of OrganicCompounds in an Electroless Glow Discharge. VI. Acetylene with UnusualCo-monomers”, 19, 2845-2858 (1975).

Based on this previous work in the field of plasma technology, theeffects of changing pressure and discharge power on the rate of plasmamodification can be understood. The rate generally decreases as thepressure is increased. Thus, as pressure increases the value of E/p, theratio of the electric field strength sustaining the plasma to the gaspressure decreases and causes a decrease in the average electron energy.The decrease in electron energy in turn causes a reduction in the ratecoefficient of all electron-molecule collision processes. A furtherconsequence of an increase in pressure is a decrease in electrondensity. Providing that the pressure is held constant, there should be alinear relationship between electron density and power.

In practice, contact lenses are surface-treated by placing them, intheir unhydrated state, within an electric glow discharge reactionvessel (e.g., a vacuum chamber). Such reaction vessels are commerciallyavailable. The lenses may be supported within the vessel on an aluminumtray (which acts as an electrode) or with other support devices designedto adjust the position of the lenses. The use of a specialized supportdevices which permit the surface treatment of both sides of a lens areknown in the art and may be used herein.

As mentioned above, the surface of the lens, for example, a siliconehydrogel continuous-wear lens is initially treated, e.g., oxidized, bythe use of a plasma to render the subsequent crosslinked polymericnetwork surface deposition more adherent to the lens. Such a plasmatreatment of the lens may be accomplished in an atmosphere composed of asuitable media, e.g., an oxidizing media such as oxygen, air, water,peroxide, O₂ (oxygen gas), etc., or appropriate combinations thereof,typically at an electric discharge frequency of about 13.56 Mhz,preferably between about 20 to about 500 watts at a pressure of about0.1 to about 1.0 torr, preferably for about 10 seconds to about 10minutes or more, more preferably about 1 to about 10 minutes. It ispreferred that a relatively “strong” plasma is utilized in this step,for example, ambient air drawn through a five percent (5%) hydrogenperoxide solution. Those skilled in the art will know other methods ofimproving or promoting adhesion for bonding of the subsequentcrosslinked polymeric network layer.

The biomedical device is then subjected to a surface treatment inaccordance with the present invention. In general, the biomedical devicesuch as a wettable silicone-based hydrogel lens is contacted with asolution containing at least one or more of crosslinked polymericnetworks of the present invention, whereby the crosslinked polymericnetwork forms a complex with the plurality of biomedical device surfacefunctional groups on the surface of the biomedical device. Thebiomedical devices can either be contacted with the solution containingat least the crosslinked polymeric networks directly in the moldassembly or the biomedical device can be released from the mold assemblyand then contacted with the solution. The solutions can be water-basedsolutions containing the crosslinked polymeric networks and render alubricious, stable, highly wettable surface. The complexation treatmentis advantageously performed under autoclave conditions.

The solutions generally include compositions for direct instillation inthe eye, including eye drop solutions and contact lens treatingsolutions distilled directly in the eye such as for rewetting a contactlens while worn as well as those that also qualify as a multi-purposesolution. Ophthalmic compositions also include compositions instilledindirectly in the eye, such as contact lens treating solutions fortreating the contact lens prior to the lens being inserted on the eye ora packaging solution for storing the lens.

The ophthalmically acceptable solutions according to the presentinvention are physiologically compatible. Specifically, the compositionsmust be “ophthalmically safe” for use with a contact lens, meaning thata contact lens treated with the solution is generally suitable and safefor direct placement on the eye without rinsing, that is, the solutionis safe and comfortable for daily contact with the eye via a contactlens that has been wetted with the solution. An ophthalmically safecomposition has a tonicity and pH that is compatible with the eye andcomprises materials, and amounts thereof, that are non-cytotoxicaccording to ISO (International Standards Organization) standards andU.S. FDA regulations. The compositions should be sterile in that theabsence of microbial contaminants in the product prior to release mustbe statistically demonstrated to the degree necessary for such products.

In general, the one or more of the crosslinked polymeric networks of thepresent invention can be present in the ophthalmic solution in an amountranging from about 0.001 to about 10% w/w and preferably from about 0.1to about 2% w/w. The ophthalmic solutions may be in the form of dropsand are useful as a component of a contact lens cleaning, disinfectingor conditioning composition containing such materials. In oneembodiment, the compositions and/or solutions of the present inventionmay be formulated as a “multi-purpose solution”. A multi-purposesolution is useful for cleaning, disinfecting, storing, and rinsing alens, particularly soft contact lenses. Multi-purpose solutions do notexclude the possibility that some wearers, for example, wearersparticularly sensitive to chemical disinfectants or other chemicalagents, may prefer to rinse or wet a contact lens with another solution,for example, a sterile saline solution prior to insertion of the lens.The term “multi-purpose solution” also does not exclude the possibilityof periodic cleaners not used on a daily basis or supplemental cleanersfor further removing proteins, for example, enzyme cleaners, which aretypically used on a weekly basis. By the term “cleaning” is meant thatthe solution contains one or more agents in sufficient concentrations toloosen and remove loosely held lens deposits and other contaminants onthe surface of a contact lens, which may be used in conjunction withdigital manipulation (e.g., manual rubbing of the lens with a solution)or with an accessory device that agitates the solution in contact withthe lens, for example, a mechanical cleaning aid.

Traditionally, multi-purpose solutions on the market have required aregimen involving mechanical rubbing of the lens with the multi-purposesolution, in order to provide the required disinfection and cleaning.Such a regimen is required under governmental regulatory authorities(e.g., the FDA or U.S. Food & Drug Administration (FDA)) for a ChemicalDisinfection System that does not qualify as a Chemical DisinfectingSolution. In one embodiment of the present invention, it is possible toformulate a cleaning and disinfecting product that, on one hand, is ableto provide improved cleaning and disinfection in the absence of arubbing regimen and, on the other hand, is gentle enough to be used as awetting agent, e.g., as an eye drop. For example, a product qualifyingas a Chemical Disinfecting Solution must meet biocidal performancecriteria established by the US FDA for Contact Lens Care Products (May1, 1997) which criteria does not involve rubbing of the lenses. In oneembodiment of the present invention, a composition is formulated to meetthe requirements of the FDA or ISO Stand-Alone Procedure for contactlens disinfecting products. Similarly, the compositions of the presentinvention can be formulated to provide enhanced cleaning without the useof a rubbing regimen. Such formulations may ensure higher patientcompliance and greater universal appeal than traditional multi-purposedisinfecting and cleaning products. A multi-purpose solution can have aviscosity of less than about 75 cps, or from about 1 to about 50 cps, orfrom about 1 to about 25 cps or at least about 95 percent weight byvolume water in the total composition.

The aqueous ophthalmic solutions may contain, in addition to the one ormore of the crosslinked polymeric networks of the present invention, oneor more antimicrobial agents, preservatives and the like. Thecompositions generally include a primary antimicrobial agent.Antimicrobial agents suitable for use in the present invention includechemicals that derive their antimicrobial activity through a chemical orphysiochemical interaction with the microbial organisms. These agentsmay be used alone or in combination.

Suitable known ophthalmically acceptable antimicrobial agents include,but are not limited to, a biguanide or a salt or free base thereof,quaternary ammonium compound or a salt thereof or free base thereof;terpene or derivative thereof, a branched, glycerol monoalkyl ether, abranched, glycerol monoalkyl amine, a branched, glycerol monoalkylsulphide, a fatty acid monoester, wherein the fatty acid monoestercomprises an aliphatic fatty acid portion having six to fourteen carbonatoms, and an aliphatic hydroxyl portion, amidoamine compound, and thelike and combinations thereof.

Suitable biguanide antimicrobial agents for use in the ophthalmiccompositions can be any biguanide or salt thereof known in the art.Representative biguanides include non-polymeric biguanides, polymericbiguanides, salts thereof, free bases thereof and the like and mixturesthereof. Representative non-polymeric biguanides are thebis(biguanides), such as alexidine, chlorhexidine, salts of alexidine,e.g., alexidine HCl, salts of chlorhexidine, alexidine free base, andthe like and mixtures thereof. The salts of alexidine and chlorhexidinecan be either organic or inorganic and are typically disinfectingnitrates, acetates, phosphates, sulfates, halides and the like.

Representative polymeric biguanides include polymeric hexamethylenebiguanides (PHMB) (commercially available from Zeneca, Wilmington,Del.), their polymers and water-soluble salts. In one embodiment,water-soluble polymeric biguanides for use herein can have a numberaverage molecular weight of at least about 1,000 or a number averagemolecular weight from about 1,000 to about 50,000. Suitablewater-soluble salts of the free bases include, but are not limited to,hydrochloride, borate, acetate, gluconate, sulfonate, tartrate andcitrate salts. Generally, the hexamethylene biguanide polymers, alsoreferred to as polyaminopropyl biguanide (PAPB), have number averagemolecular weights of up to about 100,000. Such compounds are known andare disclosed in U.S. Pat. No. 4,758,595 which is incorporated herein byreference.

PHMB is best described as a polymeric biguanide composition comprisingat least three and preferably at least six biguanide polymers, which werefer to as PHMB-A, PHMB-CG and PHMB-CGA, the general chemicalstructures of which are depicted below.

For each of these polymers, “n” represents the average number ofrepeating groups. Actually, a distribution of polymer length would existfor each of the polymers shown. The prior synthetic routes to PHMBprovided a polymeric biguanide composition with about 50% by weight ofthe polymeric composition as PHMB-CGA, that is, having a cyanoguanidinoend cap on one end and an amine on the other end, about 25% by weightPHMB-A and about 25% by weight PHMB-CG. Given this approximate weightratio of the three major PHMB polymers above, the percentage ofcyanoguardino end caps is also about 50% of the total number of terminalgroups. In this application we refer to this conventional polymericbiguanide composition as poly(hexamethylene biguanide) or PHMB.

A polymeric biguanide composition comprising less than 18 mole % ofterminal amine groups as measured by ¹³CNMR can also be used. Thepolymeric biguanide composition can also be characterized by a relativeincrease in the molar concentration of terminal guanidine groups orterminal cyanoguardino groups. For example, in one embodiment, thebiguanide composition comprises less than about 18 mole % of terminalamine groups and about 40 mol % or greater of terminal guanidine groups.In another embodiment, the biguanide composition comprises less thanabout 18 mole % of terminal amine groups and about 55 mol % or greaterof terminal guanidine groups.

In this application, we refer to this biguanide composition as PHMB-CG*.We also refer to polymeric biguanide compositions in the generic senseas “hexamethylene biguanides”, which one of ordinary skill in the artwould recognize to include both PHMB as well as PHMB-CG*.

Representative examples of suitable quaternary ammonium compounds foruse in the ophthalmic compositions of the present invention include, butare not limited to, poly[(dimethyliminio)-2-butene-1,4-diyl chloride]and[4-tris(2-hydroxyethyl)ammonio]-2-butenyl-w-[tris(2-hydroxyethyl)ammonio]-dichloride(chemical registry no. 75345-27-6) generally available as Polyquaternium1 under the tradename ONAMER® M (Stepan Company, Northfield, Ill.), andthe like and mixtures thereof.

Suitable terpene antimicrobial agents for use in the ophthalmiccompositions of the present invention include any monoterpene,sesquiterpene and/or diterpene or derivatives thereof. Acyclic,monocyclic and/or bicyclic mono-, sesqui- and/or diterpenes, and thosewith higher numbers of rings, can be used. A “derivative” of a terpeneas used herein shall be understood to mean a terpene hydrocarbon havingone or more functional groups such as terpene alcohols, terpene ethers,terpene esters, terpene aldehydes, terpene ketones and the like andcombinations thereof. Here, both the trans and also the cis isomers aresuitable. The terpenes as well as the terpene moiety in the derivativecan contain from 6 to about 100 carbon atoms and preferably from about10 to about 25 carbon atoms.

Representative examples of suitable terpene alcohol antimicrobial agentsinclude verbenol, transpinocarveol, cis-2-pinanol, nopol, isoborneol,carbeol, piperitol, thymol, α-terpineol, terpinen-4-ol, menthol,1,8-terpin, dihydro-terpineol, nerol, geraniol, linalool, citronellol,hydroxycitronellol, 3,7-dimethyl octanol, dihydro-myrcenol,tetrahydro-alloocimenol, perillalcohol, falcarindiol and the like andmixtures thereof.

Representative examples of suitable terpene ether and terpene esterantimicrobial agents include 1,8-cineole, 1,4-cineole, isobornylmethylether, rose pyran, α-terpinyl methyl ether, menthofuran,trans-anethole, methyl chavicol, allocimene diepoxide, limonenemono-epoxide, isobornyl acetate, nonyl acetate, α-terpinyl acetate,linalyl acetate, geranyl acetate, citronellyl acetate, dihydro-terpinylacetate, meryl acetate and the like and mixtures thereof.

Representative examples of terpene aldehyde and terpene ketoneantimicrobial agents include myrtenal, campholenic aldehyde,perillaldehyde, citronellal, citral, hydroxy citronellal, camphor,verbenone, carvenone, dihydro-carvone, carvone, piperitone, menthone,geranyl acetone, pseudo-ionone, α-ionine, iso-pseudo-methyl ionone,n-pseudo-methyl ionone, iso-methyl ionone, n-methyl ionone and the likeand mixtures thereof. Any other terpene hydrocarbons having functionalgroups known in the art may be used herein in the inventive composition.

In one embodiment, suitable terpenes or derivatives thereof asantimicrobial agents include, but are not limited to, tricyclene,α-pinene, terpinolene, carveol, amyl alcohol, nerol, β-santalol, citral,pinene, nerol, b-ionone, caryophillen (from cloves), guaiol,anisaldehyde, cedrol, linalool, d-limonene (orange oil, lemon oil),longifolene, anisyl alcohol, patchouli alcohol, α-cadinene, 1,8-cineole,ρ-cymene, 3-carene, ρ-8-mentane, trans-menthone, borneol, α-fenchol,isoamyl acetate, terpin, cinnamic aldehyde, ionone, geraniol (from rosesand other flowers), myrcene (from bayberry wax, oil of bay and verbena),nerol, citronellol, carvacrol, eugenol, carvone, α-terpineol, anethole,camphor, menthol, limonene, nerolidol, farnesol, phytol, carotene(vitamin A₁), squalene, thymol, tocotrienol, perillyl alcohol, borneol,simene, carene, terpenene, linalool, 1-terpene-4-ol, zingiberene (fromginger) and the like and mixtures thereof.

In one embodiment, the compound of component (ii) of the ophthalmiccomposition comprises a branched, glycerol monoalkyl ether. In anotherembodiment, the compound of component (ii) of the ophthalmic compositioncomprises a branched, glycerol monoalkyl amine. In another embodiment,the compound of component (ii) of the ophthalmic composition comprises abranched, glycerol monoalkyl sulphide. In still another embodiment, thecompound of component (ii) of the ophthalmic composition comprises anyone mixture of a branched, glycerol monoalkyl ether, a branched,glycerol monoalkyl amine or a branched, glycerol monoalkyl sulphide.

In one embodiment, the branched, glycerol monoalkyl ether for use in theophthalmic compositions of the present invention is3-[(2-ethylhexyl)oxy]-1,2-propanediol (EHOPD). In another embodiment,the branched, glycerol monoalkyl amine is3-[(2-ethylhexyl)amino]-1,2-propanediol (EHAPD). In another embodiment,the branched, glycerol monoalkyl sulphide is3-[(2-ethylhexyl)thio]-1,2-propanediol (EHSPD). In still anotherembodiment, the ophthalmic composition comprises any one mixture ofEHOPD, EHAPD and EHSPD. The chemical structures of EHOPD, EHAPD andEHSPD are provided below.

EHOPD is also referred to as octoxyglycerin and is sold under thetradename Sensiva® SC50 (Schülke & Mayr). EHOPD is a branched, glycerolmonoalkyl ether known to be gentle to the skin, and to exhibitantimicrobial activity against a variety of Gram-positive bacteria suchas Micrococcus luteus, Corynebacterium aquaticum, Corynebacteriumflavescens, Corynebacterium callunae, and Corynebacterium nephredi.Accordingly, EHOPD is used in various skin deodorant preparations atconcentrations between about 0.2 and 3 percent by weight. EHAPD can beprepared from 2-ethylhexylamine and 2,3-epoxy-1-propanediol usingchemistry well known to those of ordinary skill in the art. EHSPD can beprepared from 2-ethylhexylthiol and 2,3-epoxy-1-propanediol usingchemistry well known to those of ordinary skill in the art.

Suitable fatty acid monoester for use in the ophthalmic compositions ofthe present invention include those fatty acid monoesters comprising analiphatic fatty acid portion having six to fourteen carbon atoms, and analiphatic hydroxyl portion.

The term “aliphatic” refers to a straight or branched, saturated orunsaturated hydrocarbon having six to fourteen carbon atoms. In oneembodiment, the aliphatic fatty acid portion is a straight chain,saturated or unsaturated hydrocarbon with eight to ten carbons. Inanother embodiment, the aliphatic fatty acid portion is a branchedchain, saturated or unsaturated hydrocarbon with eight to ten carbons.

The aliphatic hydroxyl portion of the fatty acid monoester can be anyaliphatic compound with at least one hydroxyl group. In many of theembodiments, the aliphatic hydroxyl portion will have from three to ninecarbons. The aliphatic hydroxyl portion can include, but is not limitedto, propylene glycol, glycerol, a polyalkylene glycol, e.g.,polyethylene glycol or polypropylene glycol, a cyclic polyol, e.g.,sorbitan, glucose, mannose, sucrose, fructose, fucose and inositol andderivatives thereof, and a linear polyol, e.g., mannitol and sorbitoland derivatives thereof and the like and mixtures thereof.

Representative examples of suitable amidoamines for use in theophthalmic compositions of the present inventions include thoseamidoamines of the general formula: R¹⁵—(OCH₂CH₂)_(m)—X—(CH₂)_(n)—Ywherein R¹⁵ is a is C₆-C₃₀ saturated or unsaturated hydrocarbonincluding by way of example, a straight or branched, substituted orunsubstituted alkyl, alkylaryl, or alkoxyaryl group; m is zero to 16; nis 2 to 16; X is —C(O)—NR¹⁶— or —R¹⁶N—(O)—; Y is —N(R¹⁷)₂ wherein eachof R¹⁶ and R¹⁷ independently are hydrogen, a C₁-C₈ saturated orunsaturated alkyl or hydroxyalkyl, or a pharmaceutically acceptable saltthereof.

Some of the amidoamines utilized in the present invention are availablefrom commercial sources. For example, myristamidopropyl dimethylamine isavailable from Alcon Inc. (Fort Worth, Tx.) under the tradename Aldox®;lauramidopropyl dimethylamine is available from Inolex Chemical Company(Philadelphia, Pa.) under the tradename LEXAMINE® L-13; andstearamidopropyl dimethylamine is also from Inolex Chemical Company asLEXAMINE® S-13. The above-described amidoamines can be synthesized inaccordance with known techniques, including those described in U.S. Pat.No. 5,573,726.

The amount of the primary antimicrobial agent may vary depending on thespecific agent employed. For the aforementioned organicnitrogen-containing agent, typically, such agents are present inconcentrations ranging from about 0.00001 to about 0.5 wt. %, or fromabout 0.00003 to about 0.05 wt. %. For sorbic acid, higher amounts maybe required, typically about 0.01 to about 1 wt. %, or from about 0.1 toabout 0.5 wt. %. It is preferred that the antimicrobial agent is used inan amount that will at least partially reduce the microorganismpopulation in the formulations employed. If desired, the antimicrobialagent may be employed in a disinfecting amount, which will reduce themicrobial bioburden by at least two log orders in four hours and morepreferably by one log order in one hour. Most preferably, a disinfectingamount is an amount which will eliminate the microbial burden on acontact lens when used in regimen for the recommended soaking time (FDAChemical Disinfection Efficacy Test—July, 1985 Contact Lens SolutionDraft Guidelines).

The aqueous solutions may further contain one or more other componentsthat are commonly present in ophthalmic solutions, for example,surfactants, tonicity adjusting agents; buffering agents; chelatingagents; pH adjusting agents, viscosity modifying agents, and demulcentsand the like as discussed hereinabove, and which aid in makingophthalmic compositions more comfortable to the user and/or moreeffective for their intended use.

The pH of the solutions and/or compositions according to the presentinvention may be maintained within the range of pH of about 4.0 to about9.0, or about 5.0 to about 8.0, or about 6.0 to about 8.0, or about 6.5to about 7.8. In one embodiment, pH values of greater than or equal toabout 7 at most.

In one embodiment, the biomedical device is transferred to an individuallens package containing a buffered saline solution containing at leastone or more of the crosslinked polymeric networks of the presentinvention. Generally, a packaging system for the storage of anophthalmic device according to the present invention includes at least asealed container containing one or more unused ophthalmic devicesimmersed in an aqueous packaging solution. In one embodiment, the sealedcontainer is a hermetically sealed blister-pack, in which a concave wellcontaining an ophthalmic device such as a contact lens is covered by ametal or plastic sheet adapted for peeling in order to open theblister-pack. The sealed container may be any suitable generally inertpackaging material providing a reasonable degree of protection to thelens, preferably a plastic material such as polyalkylene, PVC,polyamide, and the like.

The amount of the one or more crosslinked polymeric networks employed ina packaging solution for storing an ophthalmic device in a packagingsystem of the present invention is an amount effective to improve thesurface properties of the ophthalmic device. It is believed thesecrosslinked polymeric networks enhance initial and extended comfort whena contact lens, packaged in the solution and then removed from thepackaging system, is placed on the eye for wearing. In one embodiment,the concentration of the one or more crosslinked polymeric networks inthe packaging solution will range from about 0.01 to about 20% w/w. Inone embodiment, the concentration of the one or more crosslinkedpolymeric networks present in the packaging solution will range fromabout 0.02 to about 0.1% w/w.

The packaging solutions according to the present invention arephysiologically compatible. Specifically, the solution must be“ophthalmically safe” for use with a lens such as a contact lens,meaning that a contact lens treated with the solution is generallysuitable and safe for direct placement on the eye without rinsing, thatis, the solution is safe and comfortable for daily contact with the eyevia a contact lens that has been wetted with the solution. Anophthalmically safe solution has a tonicity and pH that is compatiblewith the eye and includes materials, and amounts thereof, that arenon-cytotoxic according to ISO standards and U.S. Food & DrugAdministration (FDA) regulations.

The packaging solution should also be sterile in that the absence ofmicrobial contaminants in the product prior to release must bestatistically demonstrated to the degree necessary for such products.The liquid media useful in the present invention are selected to have nosubstantial detrimental effect on the lens being treated or cared forand to allow or even facilitate the present lens treatment ortreatments. In one embodiment, the liquid media is aqueous-based. Aparticularly useful aqueous liquid medium is that derived from saline,for example, a conventional saline solution or a conventional bufferedsaline solution.

The pH of the packaging solutions should be maintained within the rangeof about 6 to about 9, or from about 6.5 to about 7.8. Suitable buffersmay be added, such as boric acid, sodium borate, potassium citrate,citric acid, sodium bicarbonate, TRIS and various mixed phosphatebuffers (including combinations of Na₂HPO₄, NaH₂PO₄ and KH₂PO₄) andmixtures thereof. Generally, buffers will be used in amounts rangingfrom about 0.05 to about 2.5 percent by weight of the solution. In oneembodiment, buffers will be used in amounts ranging from about 0.1 toabout 1.5 percent by weight of the solution. In one embodiment, thepackaging solutions of this invention will contain a borate buffer,e.g., a borate buffer containing one or more of boric acid, sodiumborate, potassium tetraborate, potassium metaborate or mixtures thereof.

Typically, the packaging solutions are also adjusted with tonicityagents, to approximate the osmotic pressure of normal lacrimal fluidswhich is equivalent to a 0.9 percent solution of sodium chloride or 2.5percent of glycerol solution. The packaging solutions are madesubstantially isotonic with physiological saline used alone or incombination, otherwise if simply blended with sterile water and madehypotonic or made hypertonic the lenses will lose their desirableoptical parameters. Correspondingly, excess saline may result in theformation of a hypertonic solution which will cause stinging and eyeirritation.

Suitable tonicity adjusting agents include, for example, sodium andpotassium chloride, dextrose, glycerin, calcium and magnesium chlorideand the like and mixtures thereof. These tonicity adjusting agents aretypically used individually in amounts ranging from about 0.01 to about2.5% w/v. In one embodiment, the tonicity adjusting agents are used inamounts ranging from about 0.2 to about 1.5% w/v. The tonicity agentwill be employed in an amount to provide a final osmotic value of atleast about 200 mOsm/kg. In one embodiment, the tonicity adjustingagents are used in an amount to provide a final osmotic value of fromabout 200 to about 400 mOsm/kg. In one embodiment, the tonicityadjusting agents are used in an amount to provide a final osmotic valueof from about 250 to about 350 mOsm/kg. In one embodiment, the tonicityadjusting agents are used in an amount to provide a final osmotic valueof from about 280 to about 320 mOsm/kg.

If desired, one or more additional components can be included in thepackaging solution. Such additional component or components are chosento impart or provide at least one beneficial or desired property to thepackaging solution. In general, the additional components may beselected from components which are conventionally used in one or moreophthalmic device care compositions. Suitable additional componentsinclude, for example, cleaning agents, wetting agents, nutrient agents,sequestering agents, viscosity builders, contact lens conditioningagents, antioxidants, and the like and mixtures thereof. Theseadditional components may each be included in the packaging solutions inan amount effective to impart or provide the beneficial or desiredproperty to the packaging solutions. For example, such additionalcomponents may be included in the packaging solutions in amounts similarto the amounts of such components used in other, e.g., conventional,contact lens care products.

Suitable sequestering agents include, for example, disodium ethylenediamine tetraacetate, alkali metal hexametaphosphate, citric acid,sodium citrate and the like and mixtures thereof.

Suitable viscosity builders include, for example, hydroxyethylcellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, polyvinylalcohol and the like and mixtures thereof.

Suitable antioxidants include, for example, sodium metabisulfite, sodiumthiosulfate, N-acetylcysteine, butylated hydroxyanisole, butylatedhydroxytoluene and the like and mixtures thereof.

The method of packaging and storing a biomedical device such as acontact lens according to the present invention includes at leastpackaging a biomedical device immersed in the aqueous packaging solutiondescribed above. The method may include immersing the biomedical devicein an aqueous packaging solution prior to delivery to thecustomer/wearer, directly following manufacture of the contact lens.Alternately, the packaging and storing in the packaging solution mayoccur at an intermediate point before delivery to the ultimate customer(wearer) but following manufacture and transportation of the lens in adry state, wherein the dry lens is hydrated by immersing the lens in thepackaging solution. Consequently, a package for delivery to a customermay include a sealed container containing one or more unused contactlenses immersed in an aqueous packaging solution according to thepresent invention.

In one embodiment, the steps leading to the present ophthalmic devicepackaging system includes (1) molding a biomedical device in a moldcomprising at least a first and second mold portion, (2) hydrating andcleaning the biomedical device in a container comprising at least one ofthe mold portions, (3) introducing the packaging solution with the oneor more crosslinked polymeric networks into the container with thebiomedical device supported therein, and (4) sealing the container. Inone embodiment, the method also includes the step of sterilizing thecontents of the container. Sterilization may take place prior to, ormost conveniently after, sealing of the container and may be affected byany suitable method known in the art, e.g., by autoclaving of the sealedcontainer at temperatures of about 120° C. or higher.

In another embodiment, the crosslinked polymeric network of the presentinvention can be in a gel formulation. As will be readily be understoodby those skilled in the field of formulations, a gel is semisolid,suspension-type systems. Accordingly, in one embodiment, a gelformulation can include one or more of the crosslinked polymericnetworks of the present invention and one or more gel forming agents.Gel forming agents for use herein can be any gelling agent typicallyused in the art for semi solid gel dosage forms. As used herein, theterm “gelling agent” is intended to mean a compound used to render aliquid vehicle into a jelly-like vehicle. Exemplary gelling agentsinclude, by way of example and without limitation, syntheticmacromolecules, cellulose derivatives (e.g. carboxymethylcellulose andhydroxypropylmethyl-cellulose) and natural gums (e.g. tragacanth). Thesynthetic macromolecules include carbomers (e.g. Carbomer 910, 934,934P, 940, 941, and 1342), which are high molecular weight water-solublepolymers of acrylic acid crosslinked with allyl ethers of sucrose and/orpentaerythritol. Carbomers have different viscosities depending on theirpolymeric composition. Gelling agents may be selected from any ofsynthetic or semi-synthetic polymeric materials, polyacrylatecopolymers, cellulose derivatives and polymethyl vinyl ether/maleicanhydride copolymers. Various grades of Carbopol such as, for example,Carbopol 934, 940, 941, 974, 980, 981, 1342, 5984, ETD2020, ETD 2050,and Ultrez 10 (available from Noveon of Cleveland, Ohio) can be used inthe present invention. The present invention preferably includesCarbopol 980 as a gelling agent. A Carbopol is a carbomer. Generally,carbomers are synthetic high molecular weight polymer of acrylic acidthat are cross linked with either allylsucrose or allylethers ofpentaerythritol.

The gelation mechanism depends on neutralization of the carboxylic acidmoiety to form a soluble salt. The polymer is hydrophilic and producessparkling clear gels when neutralized. Carbomer gels possess goodthermal stability in that gel viscosity and yield value are essentiallyunaffected by temperature. As a topical product, carbomer gels possessoptimum rheological properties. The inherent pseudo plastic flow permitsimmediate recovery of viscosity when shear is terminated and the highyield value and quick break make it ideal for dispensing. In the presentpharmaceutical formulations, carbomer gels are used as a suspending orviscosity increasing agent. Aqueous solution of Carbopol is acidic innature due to the presence of free carboxylic acid residues.Neutralization of this solution crosslinks and gelatinizes the polymerto form a viscous integral structure of desired viscosity. The amount ofgelling agents varies widely and will ordinarily range from about 0.1%to about 10% w/w.

The gel compositions can be incorporated into wound dressings (e.g.,bandages, adhesive bandages, transdermal patches). Generally, in theseembodiments, the gel compositions are embedded within puffs, gauzes,fleeces, gels, powders, sponges, or other materials that are associatedwith a second layer to form a wound dressing. Absorption enhancers canalso be used to increase the flux of the composition, and particularlythe therapeutic protein within the composition, across the skin. Therate of such flux can be controlled by either providing a ratecontrolling membrane or dispersing the therapeutic protein in a polymermatrix or gel.

In particular embodiments, the second layer of a wound dressing can bean elastomeric layer, vapor-permeable film, waterproof film, a woven ornonwoven fabric, mesh, or the like. The composition containing layer andsecond layer can be bonded using any suitable method (e.g., theapplication of adhesives, such as pressure sensitive adhesives, hot meltadhesives, curable adhesives; the application of heat or pressure, suchas in lamination; a physical attachment through the use of stitching,studs, other fasteners; or the like).

Wound dressings may include adhesives for attachment to the skin orother tissue. Although any adhesive suitable for forming a bond with theskin or other tissue can be used, in certain embodiments a pressuresensitive adhesive is used. Pressure sensitive adhesives are generallydefined as adhesives that adhere to a substrate when a light pressure isapplied but leave little to no residue when removed. Pressure sensitiveadhesives include solvent in solution adhesives, hot melt adhesives,aqueous emulsion adhesives, calenderable adhesives, and radiationcurable adhesives.

The most commonly used elastomers in pressure sensitive adhesives caninclude natural rubbers, styrene-butadiene latexes, polyisobutylene,butyl rubbers, acrylics, and silicones. In particular embodiments,acrylic polymer or silicone-based pressure sensitive adhesives can beused. Acrylic polymers can often have a low level of allergenicity, becleanly removable from skin, possess a low odor, and exhibit low ratesof mechanical and chemical irritation. Medical grade silicone pressuresensitive adhesives can be chosen for their biocompatibility.

Amongst the factors that influence the suitability of a pressuresensitive adhesive for use in wound dressings of particular embodimentsis the absence of skin irritating components, sufficient cohesivestrength such that the adhesive can be cleanly removed from the skin,ability to accommodate skin movement without excessive mechanical skinirritation, and good resistance to body fluids.

The following examples are provided to enable one skilled in the art topractice the invention and are merely illustrative. The examples shouldnot be read as limiting the scope of the invention as defined in theclaims.

Example 1

Preparation of a crosslinked polymeric network of hyaluronic acid (HA)and chondroitin sulfate (CS) with 1,4-butanediol diglycidyl ether (BDDE)having the following general structure 1:

To a 100 mL round bottom flask fitted with magnetic stirrer was added 60mL of (reverse-osmosis) water and 3.00 g of HA (7.44 mmol based ondisaccharide unit), and 3.00 g CS (6.01 mmol based on disaccharideunit). The solution was then stirred for 15 hours to ensure completedissolution of materials to provide a clear solution having a pH of6.65. To this solution was added 1.2 mL of BDDE (6.25 mmol). After 15minutes of stirring, the pH of the slightly hazy solution was adjustedto 8.5 with 0.2 g of a 10 wt. % solution of sodium hydroxide. After 24hours the reaction mixture was then poured into 900 mL of ethanol toyield a precipitate and filtered. The solid was washed with 3×100 mL ofethanol and dried under high vacuum for 24 hours to yield 4.6 g (77%yield) of a white solid having the composition of HA, CS, branched andor crosslinked polymeric network of HA-CS, HA-HA, and CS-CS.

Analysis by size exclusion chromatography (SEC-MALS) of dialyzedmaterial indicated a weight average molecular weight of 87,500 and abranching conformation slope of 0.375 as compared to the linear analogof 0.660. Integration by NMR of the inner methylene groups of theattached BDDE against the methyl groups of the acetamide indicate 2.90mole % BDDE functionalized.

The SEC-MALS results of the crosslinked HA-CS structure 1 indicated anincrease in the molecular weight (Absolute MW via Light ScatteringDetection) as presented in Table 1 below.

TABLE 1 Mn Mw Mz Polydispersity (Daltons) (Daltons) (Daltons) (PD) HA21,200 34,000 47,400 1.60 CS 16,700 19,200 22,800 1.16 HA-CS 31,17088,940 53,610 2.85 crosslinked

Example 2

Preparation of a crosslinked polymeric network of HA and CS with adipicacid dihydrazide (ADH) having the following structure 2:

In a 50 mL Erlenmeyer flask fitted with a stir bar was added 31.9 mL of(reverse-osmosis) water along with 1.50 g of HA, (3.72 mmol based ondisaccharide unit). In a separate Erlenmeyer flask fitted with stir baradded 31.9 mL of (reverse-osmosis) water and 1.86 g of CS (3.72 mmolbased on disaccharide unit). Both solutions were stirred for 15 hours toensure complete dissolution of materials. To each solution was added0.075 g, (0.389 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride in 0.5 mL of (reverse-osmosis) water. Each container wasrinsed with 0.5 ml (reverse-osmosis) water. The solutions were allowedto stir for 5 minutes and then was added to a 100 mL round bottom flaskfitted with stir bar. The flasks were rinsed with 2 mL each(reverse-osmosis) water. To this solution was added 0.062 g (0.353 mmol)of ADH in 0.5 ml of (reverse-osmosis) water.

The pH was adjusted from 7.08 to 4.54 with 6.08 g 1N HCl. After 40minutes the pH was adjusted from 6.15 to 4.53 with 3.49 g 1N HCl. Next,after 6 hours the pH was at 4.65 and after 24 hours the pH was adjustedfrom 4.65 to 7.36 with 0.425 g of 10 wt. % sodium hydroxide. Thesolution was dialyzed using molecular weight cut-off (MWCO) 3500 in PBSbuffer, (1.0 mM), along with 100 mM sodium chloride changing out thedialysis bath every 3 hours. A total of six exchanges were done. Thethird and fourth exchanges were in 50 mM NaCl and 1 mM PBS buffer. Thelast two exchanges being done in (reverse-osmosis) water only. Asolution was lyophilized for 3 days to give 2.70 g of fluffy whitesolid, (78% yield) having the composition of HA, CS, branched and orcrosslinked polymeric network of HA-CS, HA-HA, and CS-CS.

Analysis by size exclusion chromatography (SEC_MALS) of dialyzedmaterial indicated a weight average molecular weight of 124,000 and abranching conformation slope of 0.445 as compared to the linear analogof 0.803. Integration by NMR of the inner methylene groups of theattached ADH against the methyl groups of the acetamide indicate 4.75mole % ADH functionalized.

The SEC-MALS results of the crosslinked HA-CS structure 2 indicated anincrease in the molecular weight (Absolute MW via Light ScatteringDetection) as presented in Table 2 below.

TABLE 2 Mn Mw Mz Polydispersity (Daltons) (Daltons) (Daltons) (PD) HA21,200 34,000 47,400 1.60 CS 16,700 19,200 22,800 1.16 HA-CS 40,000124,000 480,000 3.10 crosslinked

Example 3

Preparation of a linear HA mixed with a crosslinked polymeric network ofHA and CS.

The crosslinked polymeric network of HA-CS of example 1 or 2 is furthermixed with linear HA polymer chains of desired weight average molecularweight, i.e., about 10,000 to about 3,000,000 Da, to yield soft gels(crosslinked HA-CS with mixed HA chains) and then disintegrated using ahigh shear mixer, precipitated and dried. Alternatively, the crosslinkedpolymeric network of HA-CS of example 1 or 2 is mixed together withlinear HA of desired weight average molecular weight in a wt. ratio of1:1 to 1:20 (HA-CS:HA) and then dissolved in water to produce a gel forfurther use in various applications.

Example 4

A packaging solution is made by mixing the following components in therespective amounts listed in Table 3.

TABLE 3 Ingredients Parts Trizma HCl 0.627 Trizma Base 0.116 SodiumChloride 0.577 Purified Water, USP 98.680  Crosslinked HA-CS of 0.010 to1.000 Example 1 or 2 or 3 pH 3 to 6.2 Osmolality 200 to 400

Example 5

A packaging solution is made by mixing the following components in therespective amounts listed in Table 4.

TABLE 4 Ingredients Parts Trizma HCl 0.627 Trizma Base 0.116 SodiumChloride 0.577 Purified Water, USP 98.680  Crosslinked HA-CS of 0.010 to1.000 example 1 or 2 or 3 Comfort Agents 0.010 to 5.000 pH 3 to 6.2Osmolality 200 to 400

Example 6

A packaging solution is made by mixing the following components in therespective amounts listed in Table 5.

TABLE 5 Ingredients Parts Citric Acid, Anhydrous 11.320 Sodium Citrate62.220 Sodium Chloride 26.460 Purified Water, USP 100.000  CrosslinkedHA-CS of 0.010 to 1.000 Example 1 or 2 or 3 pH 3 to 6.2 Osmolality 200to 400

Example 7

A packaging solution is made by mixing the following components in therespective amounts listed in Table 6.

TABLE 6 Ingredients Parts Citric Acid, Anhydrous 11.320 Sodium Citrate62.220 Sodium Chloride 26.460 Purified Water, USP 100.000  CrosslinkedHA_CS of 0.010 to 1.000 example 1 or 2 or 3 Comfort Agents 0.010 to5.000 pH 3.0 to 6.2 Osmolality 200 to 400

Example 8

A packaging solution is made by mixing the following components in therespective amounts listed in Table 7.

TABLE 7 Ingredients Parts MOPS Sodium Salt 0.560 MOPS or 3-(N- 0.520morpholino)propanesulfonic acid Sodium Chloride 0.630 Purified Water,USP 98.280  Crosslinked HA-CS of 0.010 to 1.000 Example 1 or 2 or 3 pH6.5 to 7.9 Osmolality 200 to 400

Example 9

A packaging solution is made by mixing the following components in therespective amounts listed in Table 8.

TABLE 8 Ingredients Parts MOPS Sodium Salt 0.560 MOPS or 3-(N- 0.520morpholino)propanesulfonic acid Sodium Chloride 0.630 Purified Water,USP 98.280  Crosslinked HA-CS of 0.010 to 1.000 Example 1 or 2 or 3Comfort Agents 0.010 to 5.000 pH 6.5 to 7.9 Osmolality 200 to 400

Example 10

A packaging solution is made by mixing the following components in therespective amounts listed in Table 9.

TABLE 9 Ingredients Parts Monobasic sodium 0.015 phosphate monohydrateDibasic sodium 0.065 phosphate anhydrous Sodium Chloride 0.999 PurifiedWater, USP 99.040  Crosslinked HA-CS of 0.010 to 1.000 Example 1 or 2 or3 pH 6.0 to 8 Osmolality 200 to 400

Example 11

A packaging solution is made by mixing the following components in therespective amounts listed in Table 10.

TABLE 10 Ingredients Parts Monobasic sodium 0.015 phosphate monohydrateDibasic sodium 0.065 phosphate anhydrous Sodium Chloride 0.999 PurifiedWater, USP 99.040  Crosslinked HA-CS of 0.010 to 1.000 Example 1 or 2 or3 Comfort Agents 0.010 to 5.000 pH 6.0 to 8 Osmolality 200 to 400

Example 12

A packaging solution is made by mixing the following components in therespective amounts listed in Table 11.

TABLE 11 Ingredients Parts Sodium Borate 0.610 Boric Acid 0.098 SodiumChloride 0.886 Purified Water, USP 98.406  Crosslinked HA-CS of 0.010 to1.000 Example 1 or 2 or 3 pH 7 to 9 Osmolality 200 to 400

Example 13

A packaging solution is made by mixing the following components in therespective amounts listed in Table 12.

TABLE 12 Ingredients Parts Sodium Borate 0.610 Boric Acid 0.098 SodiumChloride 0.886 Purified Water, USP 98.406  Crosslinked HA-CS of 0.010 to1.000 Example 1 or 2 or 3 Comfort Agents 0.010 to 5.000 pH 7 to 9Osmolality 200 to 400

Example 14

Contact lenses made of Balafilcon A are cast and processed understandard manufacturing procedures. Balafilcon A is a copolymer comprisedof 3-[tris(trimethylsiloxy)silyl] propyl vinyl carbamate,N-vinyl-2-pyrrolidone (NVP),1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]polydimethylsiloxane andN-vinyloxycarbonyl alanine. All Balafilcon A lenses are air-plasmatreated prior to exposure to the crosslinked polymeric network.

For coating with the crosslinked polymeric network of Example 1, eachlens is placed in a polypropylene blister package containing 3.8-mL of a100 or 250 ppm (w/v) solution of the crosslinked polymeric networkdissolved in an appropriate buffer system, e.g., aphosphate-bufferedsaline system (PBS), a borate-buffered saline (BBS) with or withoutcontaining 300 ppm EDTA. The blister packages are sealed with a foillidstock and autoclaved at 121° C. for 30 minutes.

Example 15

Contact lenses made of Balafilcon A are cast and processed understandard manufacturing procedures. Balafilcon A is a copolymer comprisedof 3-[tris(trimethylsiloxy)silyl] propyl vinyl carbamate,N-vinyl-2-pyrrolidone (NVP),1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]polydimethylsiloxane andN-vinyloxycarbonyl alanine. All Balafilcon A lenses are air-plasmatreated prior to exposure to the crosslinked polymeric network.

For coating with the crosslinked polymeric network of Example 2, eachlens is placed in a polypropylene blister package containing 3.8-mL of a100 or 250 ppm (w/v) solution of the crosslinked polymeric networkdissolved in an appropriate buffer system, e.g., a PBS, a BBS with orwithout containing 300 ppm EDTA. The blister packages are sealed withfoil lidstock and autoclaved at 121° C. for 30 minutes.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore, the above description shouldnot be construed as limiting, but merely as exemplifications ofpreferred embodiments. For example, the functions described above andimplemented as the best mode for operating the present invention are forillustration purposes only. Other arrangements and methods may beimplemented by those skilled in the art without departing from the scopeand spirit of this invention. Moreover, those skilled in the art willenvision other modifications within the scope and spirit of the featuresand advantages appended hereto.

What is claimed is:
 1. A method of preparing a package comprising astorable, sterile ophthalmic device, the method comprising: (a)immersing an unused ophthalmic device in an aqueous packaging solutioncomprising one or more crosslinked polymeric networks, wherein the oneor more crosslinked polymeric networks comprise a reaction product of afirst glycosaminoglycan, a second glycosaminoglycan, and a firstcrosslinking agent, wherein the first glycosaminoglycan is differentthan the second glycosaminoglycan, and wherein the aqueous packagingsolution has an osmolality of at least about 180 mOsm/kg and a pH in therange of about 6 to about 9; (b) packaging the aqueous packagingsolution and the unused ophthalmic device in a manner preventingcontamination of the unused ophthalmic device by microorganisms; and (c)sterilizing the packaged aqueous packaging solution and unusedophthalmic device.
 2. The method of claim 1, wherein the firstglycosaminoglycan and the second glycosaminoglycan are independentlyselected from the group consisting of chondroitin, chondroitin sulfate,dermatan, dermatan sulfate, heparin, heparan sulfate, hyaluronan, andhyaluronic acid or a salt thereof.
 3. The method of claim 1, wherein thefirst glycosaminoglycan is hyaluronic acid and the secondglycosaminoglycan is chondroitin sulfate.
 4. The method of claim 1,wherein the first crosslinking agent is a bi- or polyfunctionalcrosslinking agent comprising two or more functional groups capable ofreacting with functional groups of the first glycosaminoglycan and thesecond glycosaminoglycan.
 5. The method of claim 1, wherein the firstcrosslinking agent comprises a bis- or polyfunctional crosslinking agentselected from the group consisting of 1,4-butanediol diglycidyl ether(BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE), ethylene glycoldiglycidyl ether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE),diepoxyoctane, 1,6-hexanediol diglycidyl ether, polypropylene glycoldiglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentylglycol diglycidyl ether, polyglycerol polyglycidyl ester, diglycerolpolyglycidyl ether, glycerol polyglycidyl ether, trimethylolpropanepolyglycidyl ether, pentaerythritol polyglyglycidyl ether, sorbitolpolyglycidyl ether, 1,2,7,8-diepoxyoctane, 1,3-butadiene diepoxide,pentaerythritol tetraglycidyl ether, and a polyepoxide.
 6. The method ofclaim 1, wherein the reaction product comprises the firstglycosaminoglycan crosslinked with the second glycosaminoglycan.
 7. Themethod of claim 6, wherein the first glycosaminoglycan crosslinked withthe second glycosaminoglycan has a weight average molecular weightranging from about 20,000 to about 6,000,000 Da.
 8. The method of claim1, wherein the one or more crosslinked polymeric networks furthercomprise a reaction product of a mixture comprising (a) the reactionproduct of the first glycosaminoglycan, the second glycosaminoglycan,and the first crosslinking agent, and (b) one or more thirdglycosaminoglycans.
 9. The method of claim 8, wherein the one or morethird glycosaminoglycans are linear hyaluronic acid or linearchondroitin sulfate having a weight average molecular weight rangingfrom about 10,000 to about 3,000,000 Da.
 10. The method of claim 8,wherein the mixture comprises from about 1 wt. % to about 20 wt. % ofthe one or more third glycosaminoglycans, based on the total weight ofthe mixture.
 11. The method of claim 1, wherein the one or morecrosslinked polymeric networks are present in the aqueous packagingsolution in a concentration of from about 0.01 to about 20% w/w.
 12. Themethod of claim 1, wherein the one or more crosslinked polymericnetworks are present in the aqueous packaging solution in aconcentration of from about 0.02 to about 0.1% w/w.
 13. The method ofclaim 1, wherein the aqueous packaging solution further comprises one ormore buffers.
 14. The method of claim 13, wherein the one or morebuffers comprise boric acid, sodium borate, potassium citrate, citricacid, sodium bicarbonate, TRIS, and a phosphate buffer.
 15. The methodof claim 1, wherein the aqueous packaging solution further comprises oneor more tonicity agents.
 16. The method of claim 15, wherein the one ormore tonicity agents are present in the aqueous packaging solution in aconcentration of from about 0.01 to about 2.5% w/v.
 17. The method ofclaim 1, wherein the aqueous packaging solution further comprises one ormore additional components.
 18. The method of claim 17, wherein the oneor more additional components comprise one or more cleaning agents,wetting agents, nutrient agents, sequestering agents, viscositybuilders, contact lens conditioning agents, and antioxidants.
 19. Themethod of claim 1, wherein the unused ophthalmic device is a contactlens.
 20. The method of claim 1, wherein the first glycosaminoglycan ishyaluronic acid or a salt thereof having a weight average molecularweight ranging from about 10,000 to about 200,000, and the secondglycosaminoglycan is chondroitin sulfate having a weight averagemolecular weight ranging from about 10,000 to about 100,000.